Prostate cancer has become the most common male cancer diagnosed in Western populations. Prostate cancer generally starts in an androgen-dependent (AD) form, which can be effectively treated with androgen ablation therapies. Androgen ablation therapies however almost always lead to more aggressive androgen-independent (AI) forms of the disease. Most research on this important issue has focused on identifying cellular and molecular changes in disease progression from AD to AI. In this application, we propose instead to focus on understanding how androgen-androgen receptor (AR) functions to promote proliferation of AD prostate cancer cells. Androgen-AR promotes both proliferation and differentiation of AD prostate cancer cells. We believe that a better understanding of how androgen-AR promotes proliferation of AD prostate cancer cells will shed light on how to specifically target the proliferation-promoting function of AR, which may lead to new treatment for AD prostate cancer that does not compromise cancer cell differentiation. This will establish a new paradigm of treating AD prostate cancer as compared to androgen ablation therapy, which inhibits both proliferation and differentiation of AD prostate cancer cells. Since functions of AR have been found important for at least some androgen-independent (AI) prostate cancer, targeting the proliferation-promoting functions of AR will impact on the treatment of AI prostate cancer as well, which is current incurable. Our hypothesis to be tested in this application is that the F-box protein Skp2 is an important downstream effector of AR in mediating proliferation of AD and some AI prostate cancer cells independently of their differentiation, and specifically targeting Skp2 represents a new concept in treatment of AD and some AI prostate cancer. In Specific Aim 1, we will determine the molecular mechanisms underlying the regulation of Skp2 by AR. In Specific Aim 2, we will determine the regulation of Skp2 by androgen in human AD prostate cancer xenografts and determine and compare the effects of castration and Skp2 knockdown on xenograft tumor growth and recurrence. Finally in Specific Aim 3, we will use mouse models to determine the role of Skp2 in prostate epithelium proliferation and transformation induced by oncogenic levels of AR, which is a suspected cause of prostate cancer in humans. PUBLIC HEALTH RELEVANCE: Prostate cancer has become the most common male cancer diagnosed in Western populations. A fundamental property of prostate cancer is its initial androgen-dependence and inevitable progression to lethal androgen-independent forms of the disease. This project aims to understand how the androgen receptor promotes prostate cancer and to develop targeted treatment strategy for prostate cancer.